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22. Differential roles of the redox-sensitive transcription factor, Nrf2 in multistage
carcinogenesis

Young-Joon Surh

Tumor Microenvironment Global Core Research Center, College of Pharmacy and Department of Molecular
Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul
National University, Seoul 08826, South Korea.

Background and aim: Nuclear factor E2-related factor 2 (Nrf2) is a redox-sensitive transcription factor
regulating the expression of a battery of genes encoding antioxidant and carcinogen detoxifying enzymes.
In contrast to its tumor suppressive functions in normal cells, Nrf2 facilitates tumor growth and progression
through metabolic reprograming in some cancer cells. Our previous study has demonstrated that
15-deoxy-Δ 12,14 -prostaglandin J and 4-hydroxyestradiol induce overactivation of Nrf2 and consequently
2
overexpression of its target protein, heme oxygenase-1 (HO-1), in human breast cancer cells.

Experimental procedure: In this study, we investigated the involvement of Nrf2 in experimentally induced
hepatocarcinogenesis by utilizing Nrf2 null mice as well as wild type animals. The liver tumor was induced
by intraperitoneal injection of diethylnitrosamine (DEN). The expression of Nrf2 and its target genes and
proteins were measured by RT-PCR and Western blot analyses. The cell proliferation was determined by
immunohistochemical analysis of Proliferating Cell Nuclear Antigen expression.

Results: Nrf2 expression, nuclear translocation, and transcriptional activity were enhanced in liver tumors.
Overactivated Nrf2 was required for hepatoma growth in DEN-induced HCC. Following DEN treatment,
Nrf2 genetic disruption reduced expression of pentose phosphate pathway-related enzymes, the depletion
of which has been associated with an amelioration of HCC incidence. Nrf2-deficient mice resisted DEN-
induced hepatocarcinogenesis.

Conclusion: The cellular stress response or cytoprotective signaling mediated via the Nrf2 is often hijacked
by cancer cells. This may facilitate the remodeling of the tumor microenvironment, making it advantageous
for the autonomic growth of cancer cells, metastasis, angiogenesis, tolerance to anticancer therapy, and self-
renewal activity of stem-like cells. Notably, Nrf2 overactivation upregulates antioxidant gene expression in
breast cancer stem cells, which contributes to the manifestation and maintenance of stemness.